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| Name | Class |
|---|---|
| Otsuka Pharmaceutical Co., Ltd. | INDUSTRY |
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The purpose of this study is to evaluate the effect of brexpiprazole, via functional magnetic resonance imaging (fMRI), on the right ventrolateral prefrontal cortex (VLPFC) activated by impulsive behavior.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Brexpiprazole 2 mg | Experimental | Brexpiprazole 2 mg/day, once daily dose, tablet, orally |
|
| Brexpiprazole 4 mg | Experimental | Brexpiprazole 4 mg/day, once daily dose, tablet, orally |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Brexpiprazole | Drug | Brexpiprazole 2 mg/day, once daily dose, tablet, orally, for 6 weeks - Brexpiprazole 4 mg/day, once daily dose, tablet, orally, for 6 weeks |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline Brain Activation in the Ventrolateral Prefrontal Cortex (VLPFC) Based on Change From Baseline to Week 6 in fMRI Blood Oxygen-level Dependent (BOLD) Activation Score in the Right VLPFC During Performance of the Go/No-go Task | To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants perform tasks designed to assess impulsivity. The tasks to be performed in the scanner included the Go/No-go. Participants were asked to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) & to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The Go trials were presented at a higher frequency (eg, 75% of the time) than the No-go trials to build up a pre-potent response/response bias. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity. | At baseline (Day 0), and week 6 (Day 42) of the treatment phase |
| Change From Baseline Brain Activation in the VLPFC Based on Change From Baseline to Week 6 in fMRI BOLD Activation Score in the Right VLPFC During Performance of the SSRT Task | To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants performed impulsivity assessment tasks. A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity. | At baseline (Day 0), and week 6 (Day 42) of the treatment phase |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to Week 3 in fMRI BOLD Activation Score in the Right VLPFC, Scanned by fMRI During Performance of Tasks Associated With Impulsivity (SSRT Task, Go/No-go Task) | Go/No-go: Participants were to press button fast to Stimulus A (neutral face) (Go trials) & to NOT press button to Stimulus B (happy face) (No-go trials). Task comprised 4 runs of 3 minutes & 8 seconds each. Each run included 36 target (Go) & 13 non target (No-go) stimuli. The stimuli were presented for 500ms with 2 to 14.5 inter-stimulus interval fixation cross in between. Target stimuli were pseudo-randomized across runs so that each participant was presented with 2 Happy Go & 2 Neutral Go conditions. SSRT: White circle was shown for 500ms, followed by left (<)/right (>) arrow. When an arrow was presented, participants were to respond fast with their index/middle finger. A titration procedure with 4 staircases that started with stop signal delay (SSD) values of 100, 150, 200 & 250ms determined participant's SSRT. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity. |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California at Irvine Medical Center | Orange | California | 92868 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32450497 | Derived | van Erp TG, Baker RA, Cox K, Okame T, Kojima Y, Eramo A, Potkin SG. Effect of brexpiprazole on control of impulsivity in schizophrenia: A randomized functional magnetic resonance imaging study. Psychiatry Res Neuroimaging. 2020 Jul 30;301:111085. doi: 10.1016/j.pscychresns.2020.111085. Epub 2020 May 5. |
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Participants had pretreatment screening phase from 2 to 21 days to assess eligibility criteria, complete screening assessments & to wash out from prior antipsychotic drugs & any other prohibited concomitant drugs; participants were followed for safety by clinic visits/telephone (after first 3 to 4 days of antipsychotic washout & weekly as needed).
The study was conducted in the United States (US). 38 participants with schizophrenia with impulsivity were enrolled (signed informed consent) and randomized (1:1): 19 participants to brexpiprazole 2mg and 4mg treatment each; received at least 1 dose of Investigational medicinal product (IMP) for 6-week treatment phase in a double-blind design.
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| ID | Title | Description |
|---|---|---|
| FG000 | Brexpiprazole 2 mg | Participants received Brexpiprazole 1 mg orally per day for 4 days followed by 2 mg per day until week 6 (Day 42)/early termination (ET) |
| FG001 | Brexpiprazole 4 mg | Participants received brexpiprazole 1 mg orally per day for 4 days followed by 2 mg per day for 3 days, 3 mg per day for 7 days and 4 mg per day until week 6 (Day 42)/ET. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Brexpiprazole 2 mg | Participants received Brexpiprazole 1 mg orally per day for 4 days followed by 2 mg per day until week 6 (Day 42)/early termination (ET) |
| BG001 | Brexpiprazole 4 mg |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline Brain Activation in the Ventrolateral Prefrontal Cortex (VLPFC) Based on Change From Baseline to Week 6 in fMRI Blood Oxygen-level Dependent (BOLD) Activation Score in the Right VLPFC During Performance of the Go/No-go Task | To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants perform tasks designed to assess impulsivity. The tasks to be performed in the scanner included the Go/No-go. Participants were asked to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) & to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The Go trials were presented at a higher frequency (eg, 75% of the time) than the No-go trials to build up a pre-potent response/response bias. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity. | All participants who had a valid baseline and a Week 6 fMRI scan assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | At baseline (Day 0), and week 6 (Day 42) of the treatment phase |
Trial visits (Days 0 to 42)
An adverse event (AE) was any untoward medical occurrence associated with use of a drug in humans, whether or not considered drug-related. Suspected adverse reaction (AR) - any AE caused by drug; in drug safety reporting, "reasonable possibility" meant to suggest a causal relationship between the drug and the AE. A serious AE (SAE) included any event that resulted in death, life-threatening, inability, hospitalization, congenital anomaly and requirement of medical/surgical intervention
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Brexpiprazole 2 mg | Brexpiprazole 2 mg/day, once daily dose, tablet, orally Brexpiprazole: Brexpiprazole 2 mg/day, once daily dose, tablet, orally, for 6 weeks - Brexpiprazole 4 mg/day, once daily dose, tablet, orally, for 6 weeks |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Clinical Development | Otsuka Data Transparency Organization | DT-inquiry@otsuka.jp |
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| ID | Term |
|---|---|
| D012559 | Schizophrenia |
| D001523 | Mental Disorders |
| D011618 | Psychotic Disorders |
| D007175 | Impulsive Behavior |
| ID | Term |
|---|---|
| D019967 | Schizophrenia Spectrum and Other Psychotic Disorders |
| D001519 | Behavior |
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| ID | Term |
|---|---|
| C000591922 | brexpiprazole |
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|
| At baseline (Day 0), and week 3 (Day 21) of the treatment phase |
| Change From Baseline to Week 6 in Barratt Impulsiveness Scale (BIS-11) | A participant-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 with higher scores indicating impulsive personality traits, and took 10 to 15 minutes to complete the BIS-11. | At baseline (Day 0), and Week 6 (Day 42) of the treatment. |
| Change From Baseline to Week 3 in BIS-11 | A participant-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 with higher scores indicating impulsive personality traits, and took 10 to 15 minutes to complete the BIS-11. | At baseline (Day 0), and Week 3 (Day 21) of the treatment. |
| Change From Baseline to Week 6 in Go/No-go Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition). Participants were instructed to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) and to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The stimuli were presented randomly. The value calculated was the rate of incorrect response for each condition (Go and No-go). | At baseline (Day 0), week 6 (Day 42) of the treatment phase |
| Change From Baseline to Week 3 in Go/No-go Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition). Participants were instructed to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) and to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The stimuli were presented randomly. The value calculated was the rate of incorrect response for each condition (Go and No-go). | At baseline (Day 0), and week 3 (Day 21) of the treatment phase |
| Change From Baseline to Week 6 in Monetary Choice Questionnaire (MCQ) Score | To measure "delay discounting" as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?"). The answers provided an estimate of the participant's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicated impulsivity. It took 5 to10 minutes to complete the MCQ | During trial visits from Day 0 to Week 6 (Day 42). |
| Change From Baseline to Week 3 in MCQ Score | To measure "delay discounting" as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?"). The answers provided an estimate of the participant's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicated impulsivity. | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in Stop Signal Reaction Time Task (SSRT) Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response | At baseline (Day 0), and Week 6 (Day 42). |
| Change From Baseline to Week 3 in SSRT Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in Continuous Performance Task (CPT) Behavior | The AX trials were "target trials" with a valid cue followed by a valid probe X. This feature was intended to encourage participants to "expect" a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with "target" responses on trials for which valid cues were presented. The cue was presented for 1000msec, the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Participants had to practice until criteria were obtained. In the AX-CPT task, the subjects were instructed to press the "Yes" button every time there is a blue letter 'X' (target) following a white letter 'A' (cue). During this task, any letter appears on the screen randomly. The value calculated was the rate of correct response for all the reaction of target trial. | During trial visits from Day 0 to Week 6 (Day 42). |
| Change From Baseline to Week 3 in CPT Behavior | The AX trials were "target trials" with a valid cue followed by a valid probe X. This feature was intended to encourage participants to "expect" a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with "target" responses on trials for which valid cues were presented. The cue was presented for 1000msec, the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Participants had to practice until criteria were obtained. In the AX-CPT task, the subjects were instructed to press the "Yes" button every time there is a blue letter 'X' (target) following a white letter 'A' (cue). During this task, any letter appears on the screen randomly. The value calculated was the rate of correct response for all the reaction of target trial. | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score | The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms. | During trial visits from Day 0 to Week 6 (Day 42). |
| Change From Baseline to Week 3 in PANSS Total Score | The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms. | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in PANSS Positive Subscale Score | PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | During trial visits from Day 0 to Week 6 (Day 42). |
| Change From Baseline to Week 3 in PANSS Positive Subscale Score | PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in PANSS Negative Subscale Score | PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | During trial visits from Day 0 to Week 6 (Day 42). |
| Change From Baseline to Week 3 in PANSS Negative Subscale Score | PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score | The severity of illness for each participant was assessed. The rater or investigator's response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. | During trial visits from Day 0 to Week 6 (Day 42). |
| Change From Baseline to Week 3 in CGI-S Score | The severity of illness for each participant was assessed. The rater or investigator's response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. | During trial visits from Day 0 to Week 3 (Day 21). |
| Clinical Global Impression - Improvement Scale (CGI-I) Score at Week 6 | To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The response at a given week was compared to the participant's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP). | During trial visits from Day 0 to Week 6 (Day 42). |
| CGI-I Score at Week 3 | To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The response at a given week was compared to the participant's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP). | During trial visits from Day 0 to Week 3 (Day 21). |
| Change From Baseline to Week 6 in Personal and Social Performance Scale (PSP) | A validated clinician-rated scale that measured personal and social functioning in 4 domains: socially useful activities (eg, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment was rated as absent, mild, manifest, marked, severe, or very severe and were converted to a total score on a 100-point scale: 71 to 100 - mild functional difficulty, 31 to 70 - manifest disabilities of various degrees and 1 to 30 - minimal functioning that required intense support and/or supervision. | During trial visits from Day 0 to Week 6 (Day 42). |
| Withdrawal by Subject |
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| Lack of Efficacy |
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Participants received brexpiprazole 1 mg orally per day for 4 days followed by 2 mg per day for 3 days, 3 mg per day for 7 days and 4 mg per day until week 6 (Day 42)/ET.
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Race | Different races were involved in this study | Number | participants |
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| Ethinicity | Number | participants |
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| ID | Title | Description |
|---|---|---|
| OG000 | Brexpiprazole 2 mg | Participants received Brexpiprazole 1 mg orally per day for 4 days followed by 2 mg per day until week 6 (Day 42)/early termination (ET) |
| OG001 | Brexpiprazole 4 mg | Participants received brexpiprazole 1 mg orally per day for 4 days followed by 2 mg per day for 3 days, 3 mg per day for 7 days and 4 mg per day until week 6 (Day 42)/ET. |
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| Primary | Change From Baseline Brain Activation in the VLPFC Based on Change From Baseline to Week 6 in fMRI BOLD Activation Score in the Right VLPFC During Performance of the SSRT Task | To evaluate the effect of brexpiprazole on brain regions activated by impulsive behavior (specifically, activation of the right VLPFC). Assessed by fMRI measurements taken when participants performed impulsivity assessment tasks. A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity. | All participants who had a valid baseline and a valid Week 3 or Week 6 fMRI scan assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | At baseline (Day 0), and week 6 (Day 42) of the treatment phase |
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| Secondary | Change From Baseline to Week 3 in fMRI BOLD Activation Score in the Right VLPFC, Scanned by fMRI During Performance of Tasks Associated With Impulsivity (SSRT Task, Go/No-go Task) | Go/No-go: Participants were to press button fast to Stimulus A (neutral face) (Go trials) & to NOT press button to Stimulus B (happy face) (No-go trials). Task comprised 4 runs of 3 minutes & 8 seconds each. Each run included 36 target (Go) & 13 non target (No-go) stimuli. The stimuli were presented for 500ms with 2 to 14.5 inter-stimulus interval fixation cross in between. Target stimuli were pseudo-randomized across runs so that each participant was presented with 2 Happy Go & 2 Neutral Go conditions. SSRT: White circle was shown for 500ms, followed by left (<)/right (>) arrow. When an arrow was presented, participants were to respond fast with their index/middle finger. A titration procedure with 4 staircases that started with stop signal delay (SSD) values of 100, 150, 200 & 250ms determined participant's SSRT. Scores were not bounded by a minimum or maximum range, higher fMRI BOLD activation scores indicate increased brain blood flow, which reflects brain activity. | All participants who had a valid baseline and a valid Week 3 fMRI scan assessment | Posted | Least Squares Mean | Standard Error | units on a scale | At baseline (Day 0), and week 3 (Day 21) of the treatment phase |
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| Secondary | Change From Baseline to Week 6 in Barratt Impulsiveness Scale (BIS-11) | A participant-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 with higher scores indicating impulsive personality traits, and took 10 to 15 minutes to complete the BIS-11. | The full analysis set consisted of all participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. Change from baseline data were presented for participant count of 16, 12 for 2mg and 4mg arms, respectively. | Posted | Least Squares Mean | Standard Error | units on a scale | At baseline (Day 0), and Week 6 (Day 42) of the treatment. |
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| Secondary | Change From Baseline to Week 3 in BIS-11 | A participant-rated scale was used to assess impulsive personality traits. The BIS-11 consisted of 30 items scored on a 4-point scale ranging from 1 (rarely/never) to 4 (almost always/ always) and the scores were used to assess 6 first-order factors (attention, motor, self-control, cognitive complexity, perseverance and cognitive instability impulsiveness) and 3 second-order factors ( motor impulsiveness, nonplanning impulsiveness and attentional impulsiveness). The total score ranged from 30 to 120 with higher scores indicating impulsive personality traits, and took 10 to 15 minutes to complete the BIS-11. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. All participants who had a valid baseline and a valid Week 3 or Week 6 fMRI scan assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | At baseline (Day 0), and Week 3 (Day 21) of the treatment. |
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| Secondary | Change From Baseline to Week 6 in Go/No-go Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition). Participants were instructed to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) and to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The stimuli were presented randomly. The value calculated was the rate of incorrect response for each condition (Go and No-go). | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Mean | Standard Deviation | Millisecond | At baseline (Day 0), week 6 (Day 42) of the treatment phase |
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| Secondary | Change From Baseline to Week 3 in Go/No-go Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in false alarm rate on the Go/No-go task (a lower false alarm rate was suggestive of better inhibition). Participants were instructed to press a button as fast as they could to Stimulus A (eg, neutral face) that appeared on the screen (Go trials) and to NOT press a button to Stimulus B (eg, happy face) that appeared on the screen (No-go trials). The stimuli were presented randomly. The value calculated was the rate of incorrect response for each condition (Go and No-go). | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Mean | Standard Deviation | Millisecond | At baseline (Day 0), and week 3 (Day 21) of the treatment phase |
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| Secondary | Change From Baseline to Week 6 in Monetary Choice Questionnaire (MCQ) Score | To measure "delay discounting" as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?"). The answers provided an estimate of the participant's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicated impulsivity. It took 5 to10 minutes to complete the MCQ | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in MCQ Score | To measure "delay discounting" as an index of impulsive behavior. It measured the extent to which the value of a reward decreased as the delay to obtaining that reward increased. The propensity of participants to delay reward was assessed with an MCQ. Discounting rate is estimated using, k= (A/V)1/D, where k is the discounting rate parameter, V is the immediate reward, A is the higher delayed reward and D is the amount of days to the delayed reward. The MCQ consisted of 27 choices between immediate and delayed rewards. The participants chose repeatedly between 2 hypothetical sums of money: a smaller amount now or a larger amount in the future (ex: ''Would you prefer $27 today or $50 in 21 days?"). The answers provided an estimate of the participant's discounting rate. The discounting rate parameter takes values between 0 and 1 and higher discounting rates indicated impulsivity. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in Stop Signal Reaction Time Task (SSRT) Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response | All participants who had a valid baseline and a valid Week 6 fMRI scan assessment | Posted | Mean | Standard Deviation | Millisecond | At baseline (Day 0), and Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in SSRT Task Behavior | Brexpiprazole reduced impulsivity was measured by a change in Stop Signal Reaction Time (SSRT) on the SSRT task (a lower SSRT was suggestive of better inhibition). A white circle was shown for 500ms, followed by a left (<)/right (>) arrow. When an arrow was presented, participants responded as fast as possible with their index/middle finger. A titration procedure with 4 staircases started with stop signal delay (SSD) values of 100, 150, 200 & 250ms to determine participant's SSRT. The tasks included 3 runs with 166 repetition times (TRs), TR=2s; 5 minutes, 32 seconds/run; 96 go trials, 32 stop trials/ run. The total task duration was 16 minutes & 36 seconds. During scanning, the SSD was dynamically adjusted to yield a 50% successful inhibition rate, so that SSRT could be estimated for each participant. This resulted in approximately equal proportions of stop trials with & without a response | All participants who had a valid baseline and a valid Week 3 fMRI scan assessment | Posted | Median | Standard Deviation | Millisecond | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in Continuous Performance Task (CPT) Behavior | The AX trials were "target trials" with a valid cue followed by a valid probe X. This feature was intended to encourage participants to "expect" a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with "target" responses on trials for which valid cues were presented. The cue was presented for 1000msec, the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Participants had to practice until criteria were obtained. In the AX-CPT task, the subjects were instructed to press the "Yes" button every time there is a blue letter 'X' (target) following a white letter 'A' (cue). During this task, any letter appears on the screen randomly. The value calculated was the rate of correct response for all the reaction of target trial. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment | Posted | Least Squares Mean | Standard Error | Rate of correct response | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in CPT Behavior | The AX trials were "target trials" with a valid cue followed by a valid probe X. This feature was intended to encourage participants to "expect" a valid probe to follow a valid cue. A consequence of this manipulation was that participants developed a prepotency to respond with "target" responses on trials for which valid cues were presented. The cue was presented for 1000msec, the inter-stimulus interval was 2000msec, and the target was presented for 500msec with a response window of 1500msec. The ITI was 1200msec. Participants had to practice until criteria were obtained. In the AX-CPT task, the subjects were instructed to press the "Yes" button every time there is a blue letter 'X' (target) following a white letter 'A' (cue). During this task, any letter appears on the screen randomly. The value calculated was the rate of correct response for all the reaction of target trial. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | Rate of correct response | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) Total Score | The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in PANSS Total Score | The PANSS consisted of 3 subscales containing 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. PANSS Positive and Negative subscale scores symptom constructs consisted of positive subscale (7 positive symptom constructs), negative subscale (7 negative symptom constructs), and general psychopathology subscale (16 symptom constructs). The possible maximum PANSS total score was 210; 30 indicating no symptoms; 210 indicating extremely severe symptoms. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in PANSS Positive Subscale Score | PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in PANSS Positive Subscale Score | PANSS consisted of positive subscales with 7 symptom constructs (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in PANSS Negative Subscale Score | PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in PANSS Negative Subscale Score | PANSS consisted of negative subscale with 7 symptom constructs (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, and stereotyped thinking). Each item was scored using a scale of 1 to 7 (a higher score indicated increased severity). The maximum subscale score was 49; 7 indicated no symptoms; 49 indicated extreme severity. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in Clinical Global Impression - Severity of Illness Scale (CGI-S) Score | The severity of illness for each participant was assessed. The rater or investigator's response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | Change From Baseline to Week 3 in CGI-S Score | The severity of illness for each participant was assessed. The rater or investigator's response choices included: 0 = not assessed; 1 = normal, not at all ill; 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Clinical Global Impression - Improvement Scale (CGI-I) Score at Week 6 | To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The response at a given week was compared to the participant's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP). | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Mean | Standard Deviation | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| Secondary | CGI-I Score at Week 3 | To assess whether the total improvement was entirely due to drug treatment. The rater or investigator's response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. The response at a given week was compared to the participant's condition at baseline (last available measurement at the baseline/Day 0 visit before the first dose of IMP). | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment. | Posted | Mean | Standard Deviation | units on a scale | During trial visits from Day 0 to Week 3 (Day 21). |
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| Secondary | Change From Baseline to Week 6 in Personal and Social Performance Scale (PSP) | A validated clinician-rated scale that measured personal and social functioning in 4 domains: socially useful activities (eg, work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. Impairment was rated as absent, mild, manifest, marked, severe, or very severe and were converted to a total score on a 100-point scale: 71 to 100 - mild functional difficulty, 31 to 70 - manifest disabilities of various degrees and 1 to 30 - minimal functioning that required intense support and/or supervision. | All participants who took at least one dose of brexpiprazole and who had a valid baseline assessment and at least one valid postbaseline efficacy assessment | Posted | Least Squares Mean | Standard Error | units on a scale | During trial visits from Day 0 to Week 6 (Day 42). |
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| 0 |
| 19 |
| 0 |
| 19 |
| 13 |
| 19 |
| EG001 | Brexpiprazole 4 mg | Brexpiprazole 4 mg/day, once daily dose, tablet, orally Brexpiprazole: Brexpiprazole 2 mg/day, once daily dose, tablet, orally, for 6 weeks - Brexpiprazole 4 mg/day, once daily dose, tablet, orally, for 6 weeks | 0 | 19 | 0 | 19 | 14 | 19 |
| Dyspepsia | Gastrointestinal disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA Preferred Ter | Non-systematic Assessment |
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| Blood creatine phosphokinase increased | Investigations | MedDRA Preferred Ter | Non-systematic Assessment |
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| Weight increased | Investigations | MedDRA Preferred Ter | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Akathisia | Nervous system disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Extrapyramidal disorder | Nervous system disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Headache | Nervous system disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Agitation | Psychiatric disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Anxiety | Psychiatric disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Insomnia | Psychiatric disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Irritability | Psychiatric disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Restlessness | Psychiatric disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Acne | Skin and subcutaneous tissue disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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| Hyperkeratosis | Skin and subcutaneous tissue disorders | MedDRA Preferred Ter | Non-systematic Assessment |
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Not provided
| At Week 6 |
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| GNG; Week 3 |
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| SSRT; Week 0 |
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| SSRT; Week 3 |
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| Superiority or Other |
| Superiority or Other |
| At Week 6 |
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| Week 3 |
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| Superiority or Other |
| Superiority or Other |
| At Week 6 |
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| At week 3 |
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| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |
| Superiority or Other |